Substituted propanol-(2) derivatives of hydroxamic acids and the use thereof as hypolipemic drugs

ABSTRACT

New 1,3-disubstituted propanol-(2) derivatives and their nicotinic acid esters of the general formula ##STR1## and their therapeutically acceptable salts, processes for preparing the same and the use thereof and pharmaceutical preparations containing the same for the treatment of hyperlipemia.

This is a division of application Ser. No. 641,982 filed Dec. 18, 1975,now U.S. Pat. No. 4,073,935.

It is already known that substituted diethers of glycerine, inparticular the glycerine ethers of phenol, exhibit therapeutic effects.Thus German Pat. No. 730,789 describes1-oxyaryloxy-3-alkoxypropanol-(2)s as sedatives and hypnotics, whileU.S. Patent 2,738,351 discloses 1,3-bisphenoxypropanol-(2)s. From GermanLetters of Disclosure 2,120,396, it is known further that1-phenoxy-3-alkoxypropanol-(2)s possess choleretic properties, whoseactivities may be varied by substitution on the phenyloxy radical, as isshown in German Letters of Disclosure 2,207,254. From J. Med. Chem.1972, p. 286, it is known that 1-phenoxy-3-arylpiperazinyl-propanol-(2)derivatives act on the central nervous system, and Japanese Pat. No.9,000,247 describes 1-oxycinnamic acid ether derivatives of3-alkylaminopropanol-(2) as compounds having beta-adrenergic activitywith nerve blocking properties.

Surprisingly, it has now been found that certain 1,3-disubstitutedpropanol-(2) derivatives and their nicotinic acid esters have potenthypolipemic properties.

It is today sufficiently established that elevated serum lipids(hypercholesterolemia and/or hypertriglyceridemia), as so-called"primary risk factors," accelerate development of atherosclerosis.Atheroselerosis, in particular atherosclerotically conditioned coronaryheart diseases, have today become the most frequent cause of death inthe highly industralized countries of the West.

This realization carries its prophylactic and therapeutic implications.The recognized risk factor of hyperlipemia must be eliminated to achievean improvement of the prognosis. Especially2-(4'-chlorophenoxy)-2-methylpropionic acid ethyl ester (Clofibrate) hasbeen introduced in the treatment of hyperlipemias. It has been found,however, that in many cases Clofibrate fails to give satisfactorytherapeutic results.

The object of the present invention was to provide new therapeuticallyvaluable compounds that, with excellent tolerance, would effectivelylower in particular the triglyceride level and/or the cholesterol levelof the blood.

The invention relates to isopropanol derivatives of general formula##STR2## and their therapeutically acceptable salts, where the X and Ylinks stand for --O--, or one of them represents --NH--, and X mayalternatively be --S-- if Y is --O--;

R¹ = --cl, or --C(CH₃)₃ ;

R² = --h,

= nicotinoyl, if X and Y stand for --O--, and X may alternatively be--S--;

A = a valence bond, vinylene or ethylene group;

R³ = --cooh,

= --coome, where Me may be sodium, potassium, magnesium as well asaluminum, or represents a therapeutically acceptable ammonium group,

= --COOR', where R' is a straight or branched, saturated or unsaturatedalkyl radical having 1 to 3 carbon atoms, optionally bearing a terminalhydroxy or methoxy group, a chlorine atom or a dimethylamino group, orthe piperidyl-(1) radical, or R' represents a pyridyl-(3)-methylradical,

= --CONHOH if X and Y stand for --O-- and X may alternatively be --S--,##STR3## where R" is a methyl or ethyl group if A represents a valencebond, X and Y stand for --O--, and X may alternatively be --S--;##STR4## if A represents a valence bond, X and Y stand for --O--, and Xmay alternatively be --S--.

The manner in which the position of the --A--R³ radical is indicated informula (1) is intended to show that this radical is in position 3 or 4relative to the Y link.

The invention relates further to a process for preparing new1,3-disubstituted propanol-(2) derivatives of general formula (1),characterized in that first, if the Y link is an oxygen atom and R³represents an alkoxycarbonyl radical, a compound of general formula##STR5## in which R¹ stands for a chlorine atom or a tertiary butylgroup and --XH for a hydroxyl, amino or mercapto group is reacted with aglycide ether of the general formula ##STR6## in which A, in position 3or 4 in relation to the oxygen atom, stands for a valence bond or avinylene or ethylene group, and R³ is an alkoxycarbonyl function of thegeneral formula --COOR' where R' is a straight or branched, saturated orunsaturated alkyl radical having 1 to 3 carbon atoms, in protic organicsolvents, preferably alcohols, whose alkyl radical is identical with R',in the presence of bases, advantageously alkali metal hydroxides, orLewis acids, for example boron trifluoride ethyl etherate; or, if the Xlink is an oxygen or sulfur atom and R³ has the meaning given forformula (3), a compound of general formula ##STR7## in which HY--represents a hydroxyl or amino group and the radical --A--R³ in position3 or 4 has the meaning given for formula (3) is reacted as describedabove with a glycide ether of the general formula ##STR8## in which R¹represents a chlorine atom or a tertiary butyl group and the X linkstands for an oxygen or sulfur atom, and the reaction product is furtherprocessed as follows to prepare other carbonyl derivatives.

To prepare the acids according to formula (1), the esters, preferablymethyl esters, according to formula (1) are advantageously saponifiedwith aqueous-alcoholic caustic alkali. From the alkali metal saltspresent in alkaline solution, the acids according to formula (1) may beset free by addition of mineral acids, as for example hydrochloric orsulfuric acid.

Preparation of the salts according to formula (1) is accomplished byallowing the corresponding acids, preferably in aqueous-alcoholicmedium, to react with bases of the alkali or alkaline earth series,aluminum bases, as well as ammonia or other therapeutically acceptableamines, by known methods.

Esters according to formula (1), where their preparation is notaccomplished on the principle described above, are obtained according tostandard methods by esterifying the carboxylic acids according toformula (1) with the corresponding alcohol using an acid catalyst, or bytransesterification, preferably the methyl esters according to formula(1) being made to react with another alcohol in the presence of an acidor alkaline catalyst.

Esters according to formula (1) in which the X and Y links stand for--O--, and X may alternatively be --S--, that are obtained neither byesterifying the carboxylic acids nor by transesterifying the methylesters according to formula (1) are preferably prepared by convertingthe carboxylic acids according to formula (1), provided with aprotective group, advantageously an acetyl or benzyl group, at thesecondary hydroxyl, using conventional halogenating agents, preferablythionyl halides, into the reactive acid halides according to formula (1)in which R³ signifies --CO--halogen, reacting the latter in manner knownper se with the corresponding alcohols, and then selectively splittingoff the protective group by hydrolysis or hydrogenolysis, depending onits nature, without at the same time causing any other irreversiblechanges in the molecule.

Compounds according to formula (1) in which the X and Y links stand for--O-- and A in position 3 or 4 represents an ethylene group and R³ is acarboxyl group or an alkoxycarbonyl group of general formula --COOR'where R' is a straight or branched, saturated alkyl radical having 1 to3 carbon atoms, may most readily be prepared by subjecting theconveniently accessible compounds according to formula (1) in which A inposition 3 or 4 is a vinylene group and R³ has the meaning given aboveto a catalytic hydrogenation, preferably using Raney nickel as catalyst.

Compounds according to formula (1) in which the X and Y links representan oxygen atom and X may alternatively be --S--, A in position 3 or 4stands for a valence bond, a vinylene or an ethylene group, and theradical R³ has the --CONHOH function, may be prepared from the estersaccording to formula (1), preferably the methyl esters, by reaction withhydroxylamine in protic medium.

Compounds according to formula (1) in which A represents a valence bondand R³ signifies an acetal radical may be prepared by reacting compoundsof general formula ##STR9## in which A in position 3 or 4 stands for avalence bond and R³ is a dimethoxymethyl, diethoxymethyl or1,3-dioxolan-(2)-yl radical with the glycide ethers according to formula(5), where advantageously the phenols according to formula (6) aregenerated during the reaction itself from the corresponding acetals.

Compounds according to formula (1) in which the radical R² represents anicotinoyl group are obtained by reacting propanol-(2) derivativesaccording to formula (1) in which the X and Y links stand for --O-- andX may alternatively be --S-- with nicotinic acid halides in a mannerknown per se. Propanol-(2) derivatives according to formula (1) in whichR³ signifies --COOH are made to react, for example in the form of theirbenzyl esters, with nicotinic acid halides, the protective group maythen be removed by selective cleavage by hydrogenolysis in the presenceof palladium charcoal.

Glycide ethers of general formula (3) may be obtained by reaction ofcompounds of the general formula ##STR10## in which A in position 3 or 4is a vinylene or ethylene group or a valence bond and R³ stands for analkoxycarbonyl function of the general formula --COOR' where R' is astraight or branched, sturated or unsaturated alkyl radical having 1 to3 carbon atoms with epihalogen hydrins, preferably epichlorhydrin, inthe presence of bases, preferably alkali metal hydroxides, isolation ofthe halogen hydrins of the general formula ##STR11## primarily formed,where A and R³ have the meaning given above, being optional.

Glycide ethers of the general formula (5) are formed in the reaction ofcompounds of the general formula ##STR12## in which R¹ represents achlorine atom or a tertiary butyl group and X an oxygen or sulfur atomwith epihalogen hydrins, preferably epichlorhydrin, in the presence ofbases, preferably alkali metal hydroxides, where the halogen hydrins ofthe general formula ##STR13## intermediately formed, where R¹ and X havethe meaning given above, need not be isolated.

Halogen hydrins according to formula (10) in which R¹ stands for achlorine atom or a tertiary butyl group and X represents an--NH--function are expediently isolated in pure form and converted intothe unstable glycide ethers in the reaction mixture by addition ofalkali metal hydroxides.

The following is a list of specific examples of carboxylic acidsaccording to the invention, but the scope of the claim according toformula (1) is not to be limited thereby:

3-(4'-Carboxyphenoxy)-1-(4'-chlorphenoxy)-propanol-(2),

3-(3'-Carboxyphenoxy)-1-(4'-chlorphenoxy)-propanol-(2),

3-[4'-(2-Carboxyvinyl)-phenoxy]-1-(4'-chlorphenoxy)-propanol-(2),

3-[3'-(2-Carboxyvinyl)-phenoxy]-1-(4'-chlorphenoxy)-propanol-(2),

3-[4'-(2-Carboxyathyl)-phenoxy]-1-(4'-chlorphenoxy)-propanol-(2),

3-[3'-(2-Carboxyathyl)-phenoxy]-1-(4'-chlorphenoxy)-propanol-(2),

3-(4'-Carboxyphenoxy)-1-(4'-t-butylphenoxy)-propanol-(2),

3-(3'-Carboxyphenoxy)-1-(4'-t-butylphenoxy)-propanol-(2),

3-[4'-(2-Carboxyvinyl)-phenoxy]-1-(4'-t-butylphenoxy)-propanol-(2),

3-[3'-(2-Carboxyvinyl)-phenoxy]-1-(4'-t-butylphenoxy)-propanol-(2),

3-[4'-(2-Carboxyathyl)-phenoxy]-1-(4'-t-butylphenoxy)-propanol-(2),

3-[3'-(2-Carboxyathyl)-phenoxy]-1-(4'-t-butylphenoxy)-propanol-(2),

3-(4'-Carboxyphenoxy)-1-(4'-chlorphenylamino)-propanol-(2),

3-(3'-Carboxyphenoxy)-1-(4'-chlorphenylamino)-propanol-(2),

3-[4'-(2-Carboxyvinyl)-phenoxy]-1-(4'-chlorphenylamino)-propanol-(2),

3-[3'-(2-Carboxyvinyl)-phenoxy]-1-(4'-chlorphenylamino)-propanol-(2),

3-[4'-(2-Carboxyathyl)-phenoxy]-1-(4'-chlorphenylamino)-propanol-(2),

3-[3'-(2-Carboxyathyl)-phenoxy]-1-(4'-chlorphenylamino)-propanol-(2)

3-(4'-Carboxyphenoxy)-1-(4'-t-butylphenylamino)-propanol-(2),

3-(3'-Carboxyphenoxy)-1-(4'-t-butylphenylamino)-propanol-(2),

3-[4'-(2-Carboxyvinyl)-phenoxy]-1-(4'-t-butylphenylamino)-propanol-(2),

3-[3'-(2-Carboxyvinyl)-phenoxy]-1-(4'-t-butylphenylamino)-propanol-(2),

3-[4'-(2-Carboxyathyl)-phenoxy]-1-(4'-t-butylphenylamino)-propanol-(2),

3-[3'-(2-Carboxyathyl)-phenoxy]-1-(4'-t-butylphenylamino)-propanol-(2),

3-(4'-Carboxyphenylamino)-1-(4'-chlorphenoxy)-propanol-(2),

3-(3'-Carboxyphenylamino)-1-(4'-chlorphenoxy)-propanol-(2),

3-[4'-(2-Carboxyvinyl)-phenylamino]-1-(4'-chlorphenoxy)-propanol-(2),

3-[3'-(2-Carboxyvinyl)-phenylamino]-1-(4'-chlorphenoxy)-propanol-(2),

3-[4'-(2-Carboxyathyl)-phenylamino]-1-(4'-chlorphenoxy)-propanol-(2),

3-[3'-(2-Carboxyathyl)-phenylamino]-1-(4'-chlorphenoxy)-propanol-(2),

3-(4'-Carboxyphenylamino)-1-(4'-t-butylphenoxy)-propanol-(2),

3-(3'-Carboxyphenylamino)-1-(4'-t-butylphenoxy)-propanol-(2),

3-[4'-(2-Carboxyvinyl)-phenylamino]-1-(4'-t-butylphenoxy)-propanol-(2),

3-[3'-(2-Carboxyvinyl)-phenylamino]-1-(4'-t-butylphenoxy)-propanol-(2),

3-[4'-(2-Carboxyathyl)-phenylamino]-1-(4'-t-butylphenoxy)-propanol-(2),

3-[3'-(2-Carboxyathyl)-phenylamino]-1-(4'-t-butylphenoxy)-propanol-(2),

3-(4'-Carboxyphenoxy)-1-(4'-chlorphenylmercapto)-propanol-(2),

3-(3'-Carboxyphenoxy)-1-(4'-chlorphenylmercapto)-propanol-(2),

3-[4'-(2-Carboxyvinyl)-phenoxy]-1-(4'-chlorphenylmercapto)-propanol-(2),

3-[3'-(2-Carboxyvinyl)-phenoxy]-1-(4'-chlorphenylmercapto)-propanol-(2),

3-[4'-(2-Carboxyathyl)-phenoxy]-1-(4'-chlorphenylmercapto)-propanol-(2),

3-[3'-(2-Carboxyathyl)-phenoxy]-1-(4'-chlorphenylmercapto)-propanol-(2),

3-(4'-Carboxyphenoxy)-1-(4'-t-butylphenylmercapto)-propanol-(2),

3-(3'-Carboxyphenoxy)-1-(4'-t-butylphenylmercapto)-propanol-(2),

3-[4'-(2-Carboxyvinyl)-phenoxy]-1-(4'-t-butylphenylmercapto)-propanol-(2),

3-[3'-(2-Carboxyvinyl)-phenoxy]-1-(4'-t-butylphenylmercapto)-propanol-(2),

3-[4'-(2-Carboxyathyl)-phenoxy]-1-(4'-t-butylphenylmercapto)-propanol-(2),

3-[3'-(2-Carboxyathyl)-phenoxy]-1-(4'-t-butylphenylmercapto)-propanol-(2),

their sodium, potassium, magnesium, aluminum, ammonium,triethanolammonium or diisopropylammonium salts, methyl,pyridyl-(3)-methyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl,2-chloroethyl, 2-piperidyl-(1)-ethyl, 2-dimethylaminoethyl, allyl,n-propyl or isopropyl esters, also the nicotinic acid esters obtainableby esterifying the secondary hydroxyl group, the hydroxamates, and thearomatic acetals according to the invention.

The compounds of general formula (1) and their salts are preferablyadministered orally. Usually the oral daily dose for adults is 0.1 to 10g, preferably 0.5 to 3 g.

The active substance may be made up for oral administration inconventional form, for example, in capsules, in liquid form, as tabletsor as powders. By mixing with solid pulverulent vehicles, such aslactose, sucrose, sorbitol, mannitol, potato or maize starch, cellulosederivatives or gelatins, with or without addition of lubricants such asfor example magnesium or calcium sterate, Carbowax® or polyethylenglycols, they may be made up into tablets or dragee centers.

Other suitable dosage forms are rod capsules, for example of hardgelatin, or closed capsules of soft gelatin with a plasticizer, as forexample glycerine. The rod capsules will preferably contain the activesubstance in granular form, for example mixed with fillers, such aslactose, sucrose, mannitol, starches such as for example potato starch,maize starch or amylopectin, cellulose derivatives, gelatins or highlydisperse silicas. In soft capsules, the active substance is preferablydissolved or suspended in suitable liquids, for example vegetable oil orliquid polyethylene glycols.

In the following, the invention will be further illustrated by somepractical examples.

EXAMPLE 13-(4'-methoxycarbonylphenoxy)-1-(4'-chlorophenoxy)-propanol-(2)

To a solution of 1.12 g (0.02 mol) potassium hydroxide in 150 ml abs.methanol is added 18.30 g (0.12 mol) 4'-hydroxybenzoic acid methyl esterand the mixture slowly heated to boiling. In the course of 1 hour, 18.46g (0.1 mol) 3-(4'-chlorophenoxy)-1,2-epoxypropane is added, and heatedfor 21 hours with reflux. Then the solvent is removed under vacuum, theresidue is taken up in ether, and washed with water to neutral reaction.After drying the organic phase over sodium sulfate and concentratingunder vacuum, there remains 25.05 g (74.4%) of crude product, which isrecrystallized from carbon tetrachloride. Colorless crystals of m.p.88°-90° C, yield 59.9%.

C₁₇ H₁₇ ClO₅ (336.78) Calc: C 60.63; H 5.09; Found: C 60.89; H 5.29

Ir-spectrum (KBr)¹) : ν(OH: 3500 cm⁻¹, ν(C═O): 1685 cm⁻¹.

¹ H-NMR-Spectrum (CDCl₃)²): 2.7 d (1) OH, 3.8 s (3) COOCH₃, 4.2 m (4)CH₂, 4.3 m (1) CHOH. 6.7 - 8.1 m (8) Aromat.

EXAMPLE 23-(4'-(2-methoxycarbonylvinyl)-phenoxy)-(4'-chlorophenoxy)-propanol-(2)

19.60 g (0.00 mols) 4'-hydroxycinnamic acid methyl ester and 18.46 (0.1mol) 3-(4'-chlorophenoxy)-1, 2-epoxypropane are heated with a solutionof 0.8 g (0.02 mol) sodium hydroxide in 150 ml absolute methanol for 18hours with reflux. After removal of the solvent under vacuum, theresidue is dissolved in chloroform and washed several times with dilutesodium hydroxide solution, then with water; the organic phase, driedover sodium sulfate and concentrated under vacuum, yields an oil thatslowly solidifies. After recrystallization, there remain 28.5 g (78.5%)colorless crystals of m.p. 83°-84° C (ethanol-water).

C₁₉ H₁₉ ClO₅ (362.82) Calc: C 62.90; H 5.28; Found: C 63.26; H 5.60

Ir-spektrum (KBr): ν(OH): 3460 cm⁻¹, ν(C═O): 1715 cm⁻¹, ν(C═C): 1635cm⁻¹.

¹ H-NMR-Spektrum (CDCl₃): 3.2 d (1) OH, 3.8 s (3) COOCH₃, 4.1 m (4) CH₂,4.2 m (1) CHOH, 6.2 d (1) CH--CO, 7.6 d (1) CH--C₆ H₄, 6.6 - 7.5 m (8)Aromat.

EXAMPLE 33-(4'-(2-methoxycarbonylvinyl)-phenoxy)-1-(4'-chlorophenylmercapto)-propanol-(2)

Into a solution of 0.56 g (0.01 mol) potassium hydroxide in 150 mlabsolute methanol, 20.07 g (0.1 mol)3-(4'-chlorophenylmercapto)-1,2-epoxypropane and 19.6 g (0.11 mol)4'-hydroxycinnamic acid methyl ester are introduced at room temperature.After heating for 19 hours with reflux, the solvent is removed undervacuum, the residue taken up in chloroform, and extracted several timeswith dil. potassium hydroxide solution. After washing and drying oversodium sulfate, the organic phase is concentrated under vacuum, yielding30.7 g (81.2%) crude product in the form of a yellow oil that graduallycrystallizes.

M.p. 103° C. (benzene).

C₁₉ H₁₉ ClO₄ S (378.88) Calc: C 60.25; H 5.05; Found: C 59.87; H 5.08

Ir-spectrum (KBr): ν(OH: 3450 cm⁻¹, ν(C═O): 1700 cm⁻¹ ν(C═C): 1630 cm⁻¹.

¹ H-NMR-Spectrum (d₆ -Aceton): 3.3 d (2) (SCH₂, 3.8 s (3) COOCH₃, 4.2 m(3) OCH₂ CH, 4.6 d (1) OH: 6.3 d (1) CH--CO, 7.5 d (1) CH--C₆ H₄, 6.8 -7.6 m (8) Aromat.

EXAMPLE 43-(4'-methoxycarbonylphenoxy)-1-(4'-chlorophenylamino)-propanol-(2)

22.01 g (0.1 mol) 3-chloro-1-(4'-chlorophenylamino)-propanol-(2),prepared by a known method (J. Am. Chem. Soc. 72, 3710, 1950), in 100 mlabsolute methanol is treated with 6.17 g (0.11 mol) potassium hydroxidein 100 ml absolute methanol. Formation of the epoxide may be observed bythe appearance of a precipitate. After adding 15.21 g (0.1 mol)4'-hydroxybenzoic acid methyl ester, the reaction mixture is heated for12 hours with reflux, the potassium chloride deposited is separated off,and the filtrate is concentrated under vacuum. The residue is digestedseveral times with water and, after drying over phosphorus pentoxide(26.4 g, 78.6%), recrystallized for further purification. Colorlesscrystals of m.p. 126°-127° (ethylacetate).

C₁₇ H₁₈ ClNO₄ (335.79) Calc. C 60.81 H 5.40 N 4.17 Found 60.35 5.29 4.26

Ir-spectrum (KBr): ν(OH, NH): 3300 cm⁻¹, ν(C═O): 1710 cm⁻¹.

¹ H-NMR-Spectrum (CDCl₃): 3.3 m (2) NCH₂, 3.8 s (3) COOCH₃, 3.9 - 4.6 m(5) NH, CHOH, OCH₂, 6.4 - 8.1 m (8) Aromat.

EXAMPLE 53-(4'-(2-methoxycarbonylvinyl)-phenoxy)-1-(4'-t-butylphenylamino)-propanol-(2)

Into a solution of 22.4 g (0.15 mol) 4'-tert. butylaniline in 100 mlmethanol is introduced dropwise, at boiling heat, 23.42 g (0.1 mol)3-(4'-(2-methoxycarbonylvinyl)-phenoxy)-1,2-epoxypropane in 100 mlmethanol. This is followed by agitating for 45 minutes with reflux,concentrating under vacuum, and separating unreacted epoxide as well asexcess amine present by fast distillation (138°/4 × 10⁻² mm). The oilyresidue crystallizes upon digesting with petroleum ether; colorlesscrystals of m.p. 114°-115° (ethylacetate/petroleum ether), yield 30.8 g(80.4%).

C₂₃ H₂₉ NO₄ (383.49) Calc: C 72.04; H 7.62; N 3.65; Found: C 71.89; H7.58; N 3.53

Ir-spectrum (KBr): ν(OH, NH): 3400 cm⁻¹ (Center of Absorption); ν(C═O);1710 cm⁻¹ ; ν(C═C): 1630 cm⁻¹.

¹ H-NMR-Spectrum (CDCl₃): 1.3 s (9) C(CH₃)₃, 3.0 - 4.5 m (7) NHCH₂CH(OH)CH₂, 3.8 s (3) COOCH₃, 6.2 d (1) CH--CO, 7.5 d (1) CH--C₆ H₄,6.5 - 7.6 m (8) Aromat.

In a manner similar to the procedures descirbed in Examples 1 to 5,other compounds of general formula (1) have been prepared, and arelisted in Table 1 below with physical characteristics. For the sake ofcompleteness, the compounds already described in the examples have beenincluded in the tables to follow.

                                      Tab. 1                                      __________________________________________________________________________     ##STR14##                                                                    No.                                                                              R.sup.1                                                                             X  Y  AR.sup.3         M.P. (° C)*                                                                         resp. B.P. (°                                                          C/mmHg)**                        __________________________________________________________________________     1 Cl    O  O  4-COOCH.sub.3    88-90        (Carbon tetrachloride)            2 Cl    O  O  4-COOCH.sub.2 CH.sub.3                                                                         74           (Ethanol/Water                    3 Cl    O  O  4-COOCH.sub.2 CHCH.sub.2                                                                       49           (Methylcyclohexane)               4 Cl    O  O  4-COOCH.sub.2 CH.sub.2 CH.sub.3                                                                57           (Ethylacetate/Petrolether)        5 Cl    O  O  4-COOCH(CH.sub.3).sub.2                                                                        72-3         (Methylcyclohexane)               6 Cl    O  O  3-COOCH.sub.3    78-9         (Cyclohexane)                     7 Cl    O  O  3-COOCH(CH.sub.3).sub.2                                                                        192 / 6 × 10.sup.-2                      8 Cl    O  O  4-CHCHCOOCH.sub.3                                                                              83-4         (Ethanol/Water)                   9 Cl    O  O  4-CH.sub.2 CH.sub.2 COOCH.sub.3                                                                56-7         (Ethylacetate/Petrolether)       10 Cl    O  O  4-CHCHCOOCH.sub.2 CH.sub.3                                                                     78-9         (Petrolether)                    11 Cl    O  O  4-CHCHCOOCH.sub.2 CHCH.sub.2                                                                   65-6         (Diisopropylether)               12 Cl    O  O  4-CHCHCOOCH.sub.2 CH.sub.2 CH.sub.3                                                            61-2         (Diisopropylether)               13 Cl    O  O  4-CHCHCOOCH(CH.sub.3).sub.2                                                                    73-4         (Diisopropylether)               14 Cl    O  O  3-CHCHCOOCH.sub.3                                                                              77           (Carbon tetrachloride)           15 Cl    O  O  3-CH.sub.2 CH.sub.2 COOCH.sub.3                                                                200 / 8 × 10.sup.-2                     16 (CH.sub.3).sub.3 C                                                                  O  O  4-COOCH.sub.3    93-4         (Methylcyclohexane)              17 (CH.sub.3).sub.3 C                                                                  O  O  4-COOCH.sub.2 CHCH.sub.2                                                                       49-50        (Diisopropylether)               18 (CH.sub.3).sub.3 C                                                                  O  O  4-COOCH.sub.2 CH.sub.2 CH.sub.3                                                                72-3         (Diisopropylether)               19 (CH.sub.3).sub.3 C                                                                  O  O  4-COOCH(CH.sub.3).sub.2                                                                        70-2         (Diisopropylether)               20 (CH.sub.3).sub.3 C                                                                  O  O  3-COOCH.sub.3    73-4         (Cyclohexane)                    21 (CH.sub.3).sub.3 C                                                                  O  O  4-CHCHCOOCH.sub.3                                                                              114          (Ethylacetate)                   22 (CH.sub.3).sub.3 C                                                                  O  O  4-CH.sub.2 CH.sub.2 COOCH.sub.3                                                                232 / 1 × 10.sup.-1                     23 (CH.sub.3).sub.3 C                                                                  O  O  4-CHCHCOOCH.sub.2 CH.sub.2 CH.sub.3                                                            71-2         (Ethylacetate-Petrolether)       24 (CH.sub.3).sub.3 C                                                                  O  O  3-CHCHCOOCH.sub.3                                                                              56           (Ethylacetate/Petrolether)       25 (CH.sub.3).sub.3 C                                                                  O  O  3-CH.sub.2 CH.sub.2 COOCH.sub.3                                                                160 / 2 × 10.sup.-2                     26 Cl    NH O  4-COOCH.sub.3    126-7        (Ethylacetate)                   27 Cl    NH O  3-COOCH.sub.3    88-9         (Ethylacetate/Petrolether)       28 Cl    NH O  4-COOCH(CH.sub.3).sub.2                                                                        124          (Ethylacetate)                   29 Cl    NH O  4-CHCHCOOCH.sub.3                                                                              128          (Petrolether)                    30 Cl    O  NH 4-COOCH.sub.3    124-5        (Methanol/Water)                 31 Cl    O  NH 4-COOCH.sub.2 CH.sub.3                                                                         110          (Petrolether)                    32 Cl    O  NH 3-COOCH.sub.2 CH.sub.3                                                                         66-7         (Ethylacetate/Petrolether)       33 (CH.sub.3).sub.3 C                                                                  O  NH 4-COOCH.sub.3    107-8        (Ethylacetate/Petrolether)       34 (CH.sub.3).sub.3 C                                                                  O  NH 3-COOCH.sub.2 CH.sub.3                                                                         170 / 1 × 10.sup.-2                     35 (CH.sub.3).sub.3 C                                                                  NH O  4-COOCH.sub.3    83-4         (Ethylacetate/Petrolether)       36 (CH.sub.3).sub.3 C                                                                  NH O  3-COOCH.sub.3    102          (Ethylacetate/Petrolether)       37 (CH.sub.3).sub.3 C                                                                  NH O  4-CHCHCOOCH.sub.3                                                                              114-5        (Ethylacetate/Petrolether)       38 Cl    S  O  4-COOCH.sub.3    67-8         (Trichlorethylen/Petrolether)                                                 7                                39 Cl    S  O  3-COOCH.sub.3    ***                                           40 CL    S  O  4-CHCHCOOCH.sub.3                                                                              103          Benzol)                          41 Cl    S  O  4-CH.sub.2 CH.sub.2COOCH.sub.3                                                                 60-1         (Ethylacetate/Petrolether)       42 Cl    S  O  3-CHCHCOOCH.sub.3                                                                              79-80        (Ethylacetate/Petrolether)       43 (CH.sub.3).sub.3 C                                                                  S  O  4-COOCH.sub.3    190 / 8 - 15 × 10.sup.-2                __________________________________________________________________________     *The melting points were determined with a Kofler melting point microscop     and are uncorrected.                                                          **Liquid products were purified with a laboratory fast distillation syste     (Leybold-Heraeus KDL 1) the boiling points given are jacket temperatures.     ***Viscous oil purfied by column chromatography.                         

EXAMPLE 63-(4'-(2-methoxyethoxycarbonyl)-vinyl)-phenoxy)-1-(4'-chlorophenoxy)-propanol-(2)

While heating, 0.56 g (0.01 mol) potassium hydroxide is dissolved in 60ml 2-methoxyethanol, and, after addition of 36.28 g (0.1 mol)3-(4'-(2-methoxycarbonylvinyl)-phenoxy)-1-(4'-chlorophenoxy)-propanol-(2),heated with reflux for 5 hours. After addition of 200 ml water, thereaction mixture is extracted repeatedly with chloroform, and thecombined organic phases are washed with water until neutral, dried oversodium sulfate and concentrated under vacuum. The oil remaining, upontreatment with acetic ester/petroleum ether, yields 21.5 g (52.8%)colorless crystals of m.p. 76°-77° C.

C₂₁ H₂₅ ClO₆ (406.8) Calc: C 62.00; H 5.70; Found: 61.67; H 5.48

Ir-spectrum (KBr): ν(OH): 3450 cm⁻¹, ν(C═O): 1690 cm⁻¹, ν(C═C): 1630cm⁻¹.

¹ H-NMR-Spectrum (CDCl₃): 3.4 s (3) OCH₃, 3.5 - 4.7 m (10) CH₂ CH(OH)CH₂CH₂ CH₂, 6.2 d (1) CH--CO, 7.6 d (1) CH--C₆ H₄, 6.6 - 7.6 m (8) Aromat.

Using the method illustrated in Example 6, other carboxylic acid estersaccording to formula (1) were prepared, as listed in Table 2.

                                      Tab. 2                                      __________________________________________________________________________     ##STR15##                                                                    No.                                                                              R.sup.1                                                                             X    Y AR.sup.3        M.P. (° C) resp. B.P. (°                                        C/mmHg)                                       __________________________________________________________________________    44 Cl    0    0 4-COOCH.sub.2 CH.sub.2 OH                                                                     92      (Benzol)                              45 Cl    0    0 4-COOCH.sub.2 CH.sub.2 OCH                                                                    71-2    (Methylcyclohexane)                   46 Cl    0    0 4-CHCHCOOCH.sub.2 CH.sub.2 OH                                                                 97-8    (Ethylacetate/Petrolether)            47 Cl    0    0 4-CHCHCOOCH.sub.2 CH.sub.2 OCH.sub.3                                                          76-77   (Ethylacetate/Petrolether)            48 (CH.sub.3).sub.3 C                                                                  0    0 4-COOCH.sub.2 CH.sub.2 OH                                                                     *                                             49 (CH.sub.3).sub.3 C                                                                  0    0 4-COOCH.sub.2 CH.sub.2 OCH.sub.3                                                              230/2 × 10.sup.-3                       50 (CH.sub.3).sub.3 C                                                                  0    0 4-CHCHCOOCH hd 2CH.sub.2 OH                                                                   240/7 × 10.sup.-2                       51 (CH.sub.3).sub.3 C                                                                  0    0 4-CHCHCOOCH.sub.2 CH.sub.2 OCH.sub.3                                                          200/4 × 10.sup.-2                       52 Cl    NH   0 4-COOCH.sub.2 CH.sub.2 OH                                                                     124- 5  (Chloroform/Methanol)                 __________________________________________________________________________     *Highly viscous oil, purified by column chromatography.                  

EXAMPLE 73-(4'-(2-carboxyvinyl)-phenoxy)-1-(4'chlorophenoxy)-propanol-(2)

A suspension of 36.28 g (0.1 mol)3-(4'-(2-methoxycarbonylvinyl)-phenoxy)-1-(4'-chlorophenoxy-propanol-(2),22.44 g (0.4 mol) potassium hydroxide, 60 ml ethanol and 30 ml water isheated for 4 hours with reflux, yielding a clear solution. The reactionmixture is then concentrated under vacuum, and the residue is dissolvedin water and adjusted to pH 1 with 5N sulfuric acid. The precipitate iswashed with water until neutral, dried over phosphorus pentoxide undervacuum and recrystallized for purification. Colorless crystals of m.p.161°-162° C (methanol), yield 31.33 g (89.7%).

C₁₈ H₁₇ ClO₅ (348.79) Calc: C 61.98; H 4.91; Found: C 61.82; H 4.83

Ir-spectrum (KBr): ν(OH): 3600 cm⁻¹ und 3080-2500 cm⁻¹, ν(C═O): 1680cm⁻¹, ν(C═C): 1630 cm⁻¹.

¹ E-NMR-Spectrum (d₆ -Aceton): 4.2 m (5) CH₂ CHCH₂, 5.3 (Center ofAbsorption) s (2) OH, COOH, 6.3 d (1) CH--CO, 7.6 d (1) CH--C₆ H₄, 6.8 -7.7 m (8) Aromat.

Using the method illustrated in Example 7, other carboxylic acidsaccording to formula (1) were prepared, as listed in Table 3.

                                      Tab. 3                                      __________________________________________________________________________     ##STR16##                              (1)                                   No.                                                                              R.sup.1                                                                            X  Y  AR.sup.3   M.P. (° C)                                    __________________________________________________________________________    53 Cl   0  0  4-COOH     181 (Ethylacetate)                                   54 Cl   0  0  3-COOH     174-5                                                                             (Ethylacetate)                                   55 Cl   0  0  4-CHCHCOOH 161-62                                                                            (Methanol)                                       56 Cl   0  0  4-CH.sub.2 CH.sub.2 COOH                                                                 111-2                                                                             (Ethylacetate/Petrolether                        57 Cl   0  0  3-CHCHCOOH 153 (Ethylacetate)                                   58 Cl   0  0  3-CH.sub.2 CH.sub.2 COOH                                                                  96 (Ethylacetate/Petrolether                        59 (CH.sub.3).sub.3 C                                                                 0  0  4-COOH     154-5                                                                             (Petrolether)                                    60 (CH.sub.3).sub.3 C                                                                 0  0  3-COOH      68-70                                                                            (Carbon tetrachloride)                           61 (CH.sub.3).sub.3 C                                                                 0  0  4-CHCHCOOH 163 (Ethylacetate)                                   62 (CH.sub.3).sub.3 C                                                                 0  0  4-CH.sub.2 CH.sub.2 COOH                                                                 102-3                                                                             (Ethylacetate/Petrolether)                       63 (CH.sub.3).sub.3 C                                                                 0  0  3-CHCHCOOH 138-40                                                                            (Ethylacetate/Petrolether)                       64 (CH.sub.3).sub.3 C                                                                 0  0  3-CH.sub.2 CH.sub.2 COOH                                                                  84-6                                                                             (Benzol/Petrolether)                             65 Cl   NH 0  4-COOH     168 (Ethylacetate)                                   66 Cl   NH 0  3-COOH     151-2                                                                             (Acetone/Water)                                  67 Cl   NH 0  4-CHCHCOOH 184-6                                                                             (Ethylacetate/Methanol)                          68 Cl   0  NH 4-COOH     164 (Methanol/Water)                                 69 Cl   0  NH 3-COOH     217-8                                                                             (Methanol)                                       70 (CH.sub.3).sub.3 C                                                                 0  NH 4-COOH     150-2                                                                             (Ethylacetate/Petrolether)                       71 (CH.sub.3).sub.3 C                                                                 0  NH 3-COOH     130-1                                                                             (Ethylacetate/Petrolether)                       72 (CH.sub.3).sub.3 C                                                                 NH 0  4-COOH     188-9                                                                             (Chloroform/Ethanol)                             73 (CH.sub.3).sub.3 C                                                                 NH 0  3-COOH     155-6                                                                             (Ethylacetate/Petrolether)                       74 (CH.sub.3).sub.3 C                                                                 NH 0  4-CHCHCOOH 171-2                                                                             (Methanol)                                       75 Cl   S  0  4-COOH     111-2                                                                             (Ethylacetate/Petrolether)                       76 Cl   S  0  3-COOH     101-3                                                                             (Acetone/Water)                                  77 Cl   S  0  4-CHCHCOOH 146 (Ethylacetate)                                   78 Cl   S  0  4-CH.sub.2 CH.sub.2 COOH                                                                  90-1                                                                             (Ethylacetate/Petrolether)                       79 Cl   S  0  3-CHCHCOOH 129-21                                                                            (Ethanol)                                        80 (CH.sub.3).sub.3 C                                                                 S  0  4-COOH     106-8                                                                             (Ethylacetate/Petrolether)                       81 (CH.sub.3).sub.3 C                                                                 S  0  4-CHCHCOOH 132-5                                                                             (Ethanol/Water)                                  __________________________________________________________________________

EXAMPLE 83-(4'-pyridyl-(3)-methoxycarbonylphenoxy)-1-(4'-chlorophenoxy)-propanol-(2)(a) 3-(4'-carboxyphenoxy)-1-(4'-chlorophenoxy)-propanol-(2) acetate

A mixture of 32.28 g (0.1 mol)3-(4'-carboxyphenoxy)-1-(4'-chlorophenoxy)-propanol-(2), 10.21 g (0.1mol) acetic anhydride and 9.16 g (0.12 mol) anhydrous pyridine isagitated for 6 hours with reflux and then concentrated under vacuum.After recrystallizing the residue from isopropanol, 35.6 g (97.6%)colorless crystals, m.p. 159°-61° C, is obtained.

Ir-spectrum (KBr): ν(OH): 3100-2540 cm⁻¹, ν(C═O): 1735 cm⁻¹, 1675 cm⁻¹.

¹ H-NMR-Spectrum (CDCl₃): 2.1 s (3) CH₃ CO, 4.2 m (4) CH₂, 5.4 m (1)CH--OCO, 6.7 - 8.1 m (9) Aromat, COOH.

(b) 3-(4'-chlorocarbonylphenoxy)-1-(4'-chlorophenoxy)-propanol-(2)acetate

A suspension of 36.48 g (0.1 mol)3-(4'-carboxyphenoxy)-1-(4'-chlorophenoxy)-propanol-(2) acetate in 200ml anhydrous chloroform is heated to boiling while agitating. The heatis then removed, and 17.85 g (0.15 mol) thionyl chloride is added so asto maintain reflux. After the exothermic reaction has subsided, heatingto boiling in continued until evolution of gas ceases (approx. 4 hours),chloroform and excess thionyl chloride are removed under vacuum, and theresidue is recrystallized from carbon tetrachloride. M.p. 81°-2° C,yield 37.0 g (96.5%).

Ir-spectrum (CHCl₃): ν(C═O): 1770⁻¹, 1735 cm⁻¹.

¹ H-NMR-Spectrum (CDCl₃): 2.1 s (3) CH₃ CO, 4.3 m (4) CH₂, 5.4 m (1)CHOCO, 6.7 - 8.1 m (8) Aromat.

(c)3-(4'-pyridyl-(3)-methoxycarbonylphenoxy)-1-(4'-chlorophenoxy)-propanol-(2

To a solution of 38.32 g (0.1 mol)3-(4'-chlorocarbonylphenoxy)-1-(4'-chlorophenoxy)-propanol-(2) acetatein 50 ml absolute benzene, 13.21 g (0.12 mol) pyridyl-(3)-methanol isadded dropwise and the mixture agitated for 5 hours with reflux. Afteraddition of 50 ml benzene, it is extracted several times with water, andthe organic phase is dried over sodium sulfate and concentrated undervacuum.

To remove the protective group, the residue is dissolved in 70 mlmethanol, treated with 20 ml conc. ammonia, and the mixture digested forseveral hours at room temperature. It is then concentrated under vacuum,and the residue is taken up in chloroform and washed with dilute sodiumhydrogen carbonate solution as well as water. After drying over sodiumsulfate, chloroform is removed under vacuum and the crude product isrecrystallized. Colorless crystals, m.p. 107°-9° C (methanol). Yield11.7 g (28.3%).

C₂₂ H₂₀ ClNO₅ (413.87) Calc: C 63.85; H 4.87; N 3.38; Found: C 63.74 H4.65; N 3.29

Ir-spectrum (KBr): ν(OH): 3210 cm⁻¹, ν(C═O): 1715 cm⁻¹.

¹ H-NMR-Spectrum (d₆ -Aceton): 4.2 m (5) CH₂ CHCH₂, 4.7 s (1) OH, 5.3 s(2) COOCH₂, 6.8 - 8.8 m (12) Aromat.

Using the method illustrated in Example 8, other carboxylic acid estersaccording to formula (1) were prepared, as listed in Table 4.

                                      Tab. 4                                      __________________________________________________________________________     ##STR17##                                                                                                   M.P. (° C)                              No.                                                                              R.sup.1                                                                            X Y AR.sup.3           resp. B.P. (° C/mmHg)                   __________________________________________________________________________    82 Cl   O O 4-COOCH.sub.2 CH.sub.2 Cl                                                                        47-9 (Cyclohexane)                             83 Cl   O O 4-COOCH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                         72-3 (Methylcyclohexane)                       84 Cl   O O                                                                                ##STR18##         99-101 (Ethylacetate/  Petrolether)            85 Cl   O O                                                                                ##STR19##         107-9 (Methanol)                               86 Cl   O O 4-CHCHCOOCH.sub.2 CH.sub.2 Cl                                     87 Cl   O O 4-CHCHCOOCH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                     104-6 (Methylcyclohexane)                      88 Cl   O O                                                                                ##STR20##         109-11 (Methylcyclohexane)                     89 Cl   O O                                                                                ##STR21##         125-6 (Ethylacetate)                           90 (CH.sub.3).sub.3 C                                                                 O O 4-COOCH.sub.2 CH.sub.2 Cl                                         91 (CH.sub.3).sub.3 C                                                                 O O 4-COOCH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                         *                                              92 (CH.sub.3).sub.3 C                                                                 O O                                                                                ##STR22##                                                        93 (CH.sub.3).sub.3 C                                                                 O O                                                                                ##STR23##                                                        __________________________________________________________________________     *Viscous oil, purified by column chromatography.                         

EXAMPLE 93-(4'-(2-methoxycarbonylvinyl)-phenoxy)-1-(4'-chlorophenoxy)-propanol-(2)nicotinic acid ester

36.28 g (0.1 mol)3-(4'-(2-methoxycarbonylvinyl)-phenoxy)-1-(4'-chlorophenoxy)-propanol-(2)and 17.80 g (0.1 mol) nicotinic acid chloride hydrochloride are treatedwith 100 ml absolute pyridine and agitated for 14 hours with reflux.After removal of precipitate, the pyridine is distilled off undervacuum, the residue is taken up in ether, the ether phase is extractedrepeatedly with water, dried over sodium sulfate and concentrated undervacuum. Further purification of the crude product is accomplished bycolumn chromatography (silica gel 60 Merck, traveling mediumbenzene/ether 3/1); subsequent treatment of the product with petroleumether yields 18.15 g (39.0%) colorless crystals of m.p. 110°-112° C(isopropanol).

C₂₅ H₂₂ ClNO₆ (467.92) Calc: C 64.17; H 4.74; N 2.99; Found: C 63.69; H4.71; N 3.19

Ir-spectrum (CHCl₃): ν(C═O): 1710 cm⁻¹ (Schwerpunkt), ν(C═C): 1635 cm⁻¹.

¹ H-NMR-Spectrum (CCl₄): 3.7 s (3) COOCH₃, 4.3 m (4) CH₂, 5.7 m (1),CHOCO, 6.2 d (1) CH--CO, 7.6 d (1) CH--C₆ H₄, 6.6 - 9.2 m (12) Aromat.

Using the method illustrated in Example 9, other nicotinic acid estersaccording to formula (1) were similarly prepared, as listed in Table 5.

                                      Tab. 5                                      __________________________________________________________________________     ##STR24##                                                                    No. R.sup.1                                                                            X Y AR.sup.3   M.P. (° C) resp. B.P. (° C/mmHg)        __________________________________________________________________________    94  Cl   0 0 4-COOH                                                           95  Cl   0 0 4-COOCH.sub.3                                                                            200 / 1 × 10.sup.-2                             96  Cl   0 0 4-COOCH(CH.sub.3).sub.2                                                                  137 / 7 × 10.sup.-2                             97  Cl   0 0 4-CHCHCOOH                                                       98  Cl   0 0 4-CHCHOOOCH.sub.3                                                                        110-12 (Isopropanol)                                  99  Cl   0 0 4-CH.sub.2 CH.sub.2 COOCH.sub.3                                                          101-3 (Methanol/Water                                 100 Cl   0 0 3-CH.sub.2 CH.sub.2 COOCH.sub.3                                                          *                                                     101 (CH.sub.3).sub.3 C                                                                 0 0 4-COOH                                                           102 (CH.sub.3).sub.3 C                                                                 0 0 4-COOCH.sub.3                                                                            133-4 (Methanol)                                      103 (CH.sub.3).sub.3 C                                                                 0 0 4-CHCHCOOCH.sub.3                                                                        106-0 (Methanol/Water                                 104 Cl   S 0 4-COOCH.sub.3                                                                            *                                                     __________________________________________________________________________     *Highly viscous oil, purified by columm chromatography.                  

EXAMPLE 103-(4'-(2-(n-hydroxycarbamoyl)-vinyl)-phenoxy)-1-(4'-chlorophenoxy)-propanol-(2)

13.9 g (0.2 mol) hydroxylamine hydrochloride and 13.33 g (0.3 mol)sodium hydroxide are dissolved in 200 ml aqueous ethanol (1:1). To thisis added dropwise 36.28 g (0.1 mol)3-(4'-(2-methoxycarbonylvinyl)-phenoxy)-1-(4'-chlorophenoxy)-propanol-(2)in 200 ml ethanol, and the mixture is agitated for 5 hours with reflux.After concentrating to dryness under vacuum, the residue is taken up in250 ml water, the solution is acidified with dilute hydrochloric acid,and the precipitate is separated off and dried over phosphoruspentoxide. Colorless crystals of m.p. 108°-10° C (acetonewater). Yield28.4 g (78.2%).

C₁₈ H₁₈ ClNO₅ (363.81) Calc: C 59.43; H 4.98; Found: C 59.36; H 5.06

Ir-spectrum (KBr): ν(OH, NH): 3580-2700 cm⁻¹, ν(C═O): 1655 cm⁻¹, ν(C═C):1625 cm⁻¹.

¹ H-NMR-Spectrum (d₆ -DMSO): 3,5 (Schwerpunkt) s (2) und 5.4(Schwerpunkt) s (1) CHOH, NHOH, 4.1 m (5) CH₂ CHCH₂, 6.3 d (1) CHCO, 7.5d (1) CH--C₆ H₄, 6.7 - 7.6 m (8) Aromat.

Using the method illustrated in Example 10, other carboxylic acidhydroxamates according to formula (1) were prepared, as listed in Table6.

                                      Tab. 6                                      __________________________________________________________________________     ##STR25##                                                                    No.                                                                              R.sup.1                                                                            X Y A-R.sup.3   M.P.  (° C)                                    __________________________________________________________________________    105                                                                              Cl   O O 4-CONHOH    158-60 (Methanol/Water)                               106                                                                              Cl   O O 4-CHCHCONHOH                                                                              108-10 (Acetone/Water)                                107                                                                              Cl   O O 4-CH.sub.2 CH.sub.2 CONHOH                                                                120-1 (Ethylacetate)                                  108                                                                              (CH.sub.3).sub.3 C                                                                 O O 4-CONHOH    133-35 (Methanol/Water)                               109                                                                              Cl   S O 4-CH.sub.2 CH.sub.2 CONHOH                                                                98-9 (Ethylacetate/Petrolether)                       __________________________________________________________________________

EXAMPLE 113-(4'-(1,3-dioxolan-2-yl)-phenoxy)-1-(4'-chlorophenoxy)-propanol-(2)

A solution of 20.82 g (0.1 mol) 2-(4'-acetoxyphenyl)-1,3-dioxolane(prepared analogously to the method given in Bull. Soc. Chim. France1972 (6), 2287) and 6.74 g (0.12 mol) potassium hydroxide in 100 mlisopropanol is treated in the course of 1 hour with 1.8 ml (0.1 mol)water and agitated for 3 hours at room temperature. Then 16.56 g (0.09mol) 3-(4'-chlorophenoxy)-1,2-epoxypropane is added and the reactionmixture kept at 60° C for another 6 hours. After concentrating thesolvent under vacuum, the residue is taken up in ether, and the etherealphase is extracted several times with 2% potassium carbonate solution,washed with water until neutral, and dried over sodium sulfate. Theether is removed under vacuum and the residue (20.9 g, 66.4%) distilledat 190° C and 1 × 10⁻¹ mm. Colorless crystals, m.p. 58°- 60° C(petroleum ether).

C₁₈ H₁₉ ClO₅ (350.78): Calc: C 61.63; H 5.46; Found: C 61.56; H 5.48

Ir-spectrum (KBr): ν(OH): 3465 cm⁻¹, ν(C--O--C--O--C): 1030-1170 cm⁻¹

¹ H-NMR-Spectrum (CCl₄): 3.5 - 4.5 m (10) CH₂ CH(OH)CH₂, CH₂ CH₂, 5.6 s(1) CH--C₆ H₄, 6.5 - 7.4 m (8) Aromat.

Using the method illustrated in Example 11, other acetals according toformula (1) were prepared, as listed in Table 7.

                                      Tab. 7                                      __________________________________________________________________________     ##STR26##                                                                    No. R.sup.1                                                                            X Y A-R.sup.3 M.P.(° C) resp. B.P.(° C/mmHg)           __________________________________________________________________________    110 Cl   O O 4-CH(OCH.sub.2 CH.sub.3).sub.2                                                          175/4 × 10.sup.-3                                111 Cl   O O                                                                                ##STR27##                                                                              58-60 (Petrolether)                                    112 Cl   O O                                                                                ##STR28##                                                                              178/4 × 10.sup.-3                                113 (CH.sub.3).sub.3 C                                                                 O O 4-CH(OCH.sub.3).sub.2                                                                   185 / 3 × 10.sup.-2                              114 (CH.sub.3).sub.3 C                                                                 O O                                                                                ##STR29##                                                                              200 / 3 × 10.sup.-3                              115 (CH.sub.3).sub.3 C                                                                 O O                                                                                ##STR30##                                                                              170 / 3 × 10.sup.-3                              116 Cl   S O 4-CH(OCH.sub.3).sub.2                                                                   165 / 4 × 10.sup.-3                              117 Cl   S O                                                                                ##STR31##                                                                              180/ 4 × 10.sup.-3                               118 Cl   S O                                                                                ##STR32##                                                                              175 / 3 × 10.sup.-3                              __________________________________________________________________________

EXAMPLE 12 Medicinal drug containing3-(4'-methoxycarbonylphenoxy)-1-(4'-chlorophenoxy)-propanol-(2)

100 g 3-(4'-methoxycarbonylphenoxy)-1-(4'-chlorophenoxy)-propanol-(2) iswell mixed with 16 g maize starch and 6 g highly disperse silicondioxide, then moistened with a solution of 2 g stearic acid, 6 gacetylcellulose and 6 g stearin in 70 ml isopropanol and granulated. Thedried granulate is put through a sieve and, after mixing with 16 g maizestarch, 16 g talc and 2 g magnesium stearate, molded into 1000 drageecenters. After coating with a sirup of 2 g lacca, 7.5 g gum arabic, 0.15g coloring, 2 g colloidal silicon dioxide, 25 g talc and 53.55 gsucrose, and drying, a thousand dragees each weighing 260 mg andcontaining 100 mg active substance are obtained.

EXAMPLE 13 Medicinal drug containing3-(4'-carboxyphenoxy)-1-(4'-tert.-butylphenoxy)-propanol-(2)

250 g pulverized3-(4'-carboxyphenoxy)-1-(4'-tert.-butylphenoxy)-propanol-(2) is mixedwith 250 g lactose and 75 g starch, then treated with 16.5 g talc and6.5 g calcium stearate, and, after mixing thoroughly, capsuled in onethousand hard gelatin capsules of suitable size, so that each capsulecontains 250 mg active substance.

EXAMPLE 14 Medicinal drug containing3-(4'-(2-methoxycarbonylethyl)-phenoxy)-1-(4'-tert.-butylphenoxy)-propanol-(2)

500 g3-(4'-(2-methoxycarbonylethyl)-phenoxy)-1-(4'-tert.-butylphenoxy)-propanol-(2)is mixed with 500 g polyethylene glycol and packed in two thousand ovalcapsules of 500 mg capacity by the Scherer process.

EXAMPLE 15 Medicinal drug containing3-(4'-methoxycarbonylphenoxy)-1-(4'-chlorophenoxy)-propanol-(2)nicotinic acid ester

500 g 3-(4'-methoxycarbonylphenoxy)-1-(4'-chlorophenoxy)-propanol-(2)nicotinic acid ester is mixed with 500 g vegetable oil and packed in twothousand soft gelatin capsules (7.5) of 500 mg capacity by the Schererprocess.

EXAMPLE 16 Pharmacological Testing

1. Oral tolerance

After oral administration of the test compounds to mice of strain NMR-I,weight 15-20 g, the acute toxicity was determined. LD₅₀ values werecalculated following Litchfield-Wilcoxon (J. Pharmak. Exp. Therap. 96,99, 1949) and pertain to the 8th day after treatment.

The LD₅₀ for clofibrate was 1900 mg/kg. The substances according to theinvention were better tolerated and superior to clofibrate throughout.

2. Lipid-lowering action

Lipid-lowering action was tested on groups of 10 male Wistar rats(Ivanovas-Kisslegg), weight 200-220 g, normolipemic, on ordinary ration("ssniff" complete feed).

The test compounds were taken up in an aqueous solution of 0.25% agarand 0.85% NaCl and administered orally. After administration of 4 × 100mg/kg over a period of 3 days, the animals were bled by cardiac punctureafter privation of food for 4 hours.¹

Serum lipids were determined with a Technicon autoanalyzer. Totalcholesterol (TC) was tested by the Liebermann-Burchard reaction.Quantitative analysis for triglycerides (TG) was performed by Eggsteinand Kreutz's enzyme method (Klin. Wschr. 44, 262, 1966), modified forautoanalyzer.

Lipid lowering effect is expressed as percent lowering of totalcholesterol and triglycerides compared to controls. Under theexperimental conditions given above, clofibrate achieved an averagelowering of total cholesterol by 37.4 ± 13.6% and of triglycerides by50.4 ± 20.0% (X ± S_(x) in each instance).¹ All compounds tested weresuperior to clofibrate in at least one score.

                  Table 8.                                                        ______________________________________                                        Percent lowering of triglycerides (TG) and total                              cholesterol (TC) levels in rat serum after oral admin-                        istration of test substances.                                                            % Lowering                                                         Compound     TG            TC                                                 Number       --X ± S.sub.x                                                                            --X ± S.sub.x                                   ______________________________________                                         1           63.8 ± 17.2                                                                              47.9 ± 10.2                                      2           60.2 ±  8.4                                                                              40.4 ± 24.3                                      3           68.6 ± 11.0                                                                              35.9 ± 18.1                                      4           74.2 ± 13.4                                                                              53.0 ±  7.5                                      5           54.6 ± 28.3                                                                              15.5 ± 14.7                                      6           78.1 ± 11.2                                                                              28.5 ± 10.0                                      7           73.2 ±   8.3                                                                             32.1 ± 18.1                                      8           52.1 ±   7.7                                                                             17.3 ± 26.0                                      9           87.9 ± 11.9                                                                              44.5 ± 17.5                                     10           77.4 ±  8.5                                                                              38.4 ±  5.6                                     11           40.2 ± 10.3                                                                              76.1 ±  3.7                                     12           67.0 ± 15.7                                                                              40.3 ± 10.8                                     13           79.7 ± 10.4                                                                              50.1 ±  7.3                                     14           64.8 ±  17.7                                                                             22.9 ±  5.2                                     17           83.4 ±   8.8                                                                             55.8 ±   7.1                                    18           68.3 ± 23.1                                                                              34.4 ±   6.9                                    19           72.9 ±   6.1                                                                             44.9 ±   8.0                                    22           79.0 ± 10.7                                                                              46.9 ± 11.4                                     23           77.9 ±  5.5                                                                              40.9 ±  9.3                                     26           81.0 ±  5.2                                                                              25.8 ± 23.7                                     28           64.6 ± 16.9                                                                              30.8 ±  9.7                                     29           62.3 ± 10.7                                                                              12.7 ± 12.5                                     30           69.3 ± 15.9                                                                              12.1 ±  8.6                                     31           63.6 ± 18.5                                                                              33.3 ± 17.6                                     35           79.2 ±  9.0                                                                              51.9 ±  9.3                                     37           71.9 ± 13.5                                                                              32.8 ± 13.7                                     38           53.0 ± 17.6                                                                              12.3 ± 14.6                                     40           59.4 ± 14.7                                                                               9.6 ±  9.1                                     43           71.0 ± 12.5                                                                              37.2 ± 13.8                                     45           75.8 ± 17.1                                                                              51.7 ± 12.2                                     46           69.5 ±  8.9                                                                              32.3 ± 19.7                                     47           57.8 ± 10.7                                                                              44.4 ± 18.0                                     48           85.5 ± 15.6                                                                              60.4 ±  6.7                                     49           76.1 ±  14.6                                                                             33.1 ± 16.7                                     50           84.2 ±  5.4                                                                              49.3 ± 11.7                                     51           77.0 ±  7.4                                                                              47.8 ± 10.4                                     52           53.9 ± 13.3                                                                              50.0 ± 10.0                                     53           83.6 ± 15.5                                                                              40.5 ± 13.5                                     54           80.0 ± 11.4                                                                              28.7 ± 10.2                                     55           49.9 ± 23.7                                                                              45.4 ±  9.2                                     56           76.7 ±  7.7                                                                              48.0 ± 12.9                                     57           61.8 ± 10.9                                                                              28.4 ± 11.1                                     58           71.3 ±  7.6                                                                              42.2 ±  5.6                                     59           66.7 ±  8.1                                                                              45.7 ± 14.3                                     61           81.2 ± 17.1                                                                              44.9 ± 13.8                                     62           91.9 ±  5.0                                                                              38.7 ± 15.0                                     65           72.9 ± 11.3                                                                              20.9 ± 13.7                                     68           54.1 ± 17.0                                                                              15.2 ± 10.0                                     70           78.1 ± 10.4                                                                              33.3 ± 12.2                                     71           58.4 ± 15.5                                                                              28.9 ±  9.5                                     72           75.1 ±  9.9                                                                              53.7 ± 10.4                                     74           69.7 ±  9.6                                                                              50.7 ±  6.4                                     75           55.8 ± 14.2                                                                              32.2 ±  8.7                                     77           77.8 ± 12.0                                                                              55.5 ± 12.7                                     80           71.6 ± 18.6                                                                              48.2 ± 11.6                                     81           58.7 ± 14.8                                                                              27.5 ± 12.7                                     82           83.8 ±  6.0                                                                              53.9 ±  9.1                                     83           72.5 ± 11.1                                                                              46.2 ± 15.4                                     85           81.4 ±  5.9                                                                              52.0 ±  8.6                                     95           63.8 ± 14.8                                                                              38.3 ± 15.4                                     96           74.0 ±  4.8                                                                              36.8 ± 14.3                                      104         81.1 ±  5.6                                                                              48.0 ±  7.9                                      105         53.2 ± 11.2                                                                              29.8 ± 14.3                                      106         64.2 ± 17.1                                                                              43.9 ± 19.4                                      107         84.8 ±  4.1                                                                              49.6 ± 13.3                                      108         77.8 ±  3.3                                                                              51.1 ±  8.3                                      110         68.0 ±  6.5                                                                              32.1 ± 15.8                                      113         84.0 ±  8.8                                                                              44.4 ± 11.2                                      114         91.6 ±  4.8                                                                              67.9 ±  6.6                                      116         74.0 ±  9.8                                                                              43.2 ±  9.8                                     ______________________________________                                    

We claim:
 1. A 1,3-disubstituted propanol-(2) derivative of the generalformula ##STR33## or its therapeutically acceptable salt, where X and Ystand for --O--; R¹ = --Cl, or --C(CH₃)₃ ;R² = --h; a = a valence bond,a vinylene group, or an ethylene group; R³ = --conhoh.
 2. the compoundof claim 1, where X and Y stand for --O--;R¹ = --cl, or --C(CH₃)₃ ; R² =--h; a = a valence bond; R³ = --conhoh. 3.3-(4'-(n-hydroxycarbamoyl)-phenoxy)-1-(4'-t.-butylphenoxy)-propanol-(2).4. A medicinal composition, for the treatment of hyperlipemia containingan effective amount of a compound according to claim 1 as the activesubstance together with a pharmaceutically acceptable carrier. 5.Medicinal composition according to claim 4, characterized in that thesingle dose of the particular medicinal form contains 10-500 mg activesubstance.
 6. A medicinal composition according to claim 5, wherein theactive substance is3-(4'-(N-hydroxycarbamoyl)-phenoxy)-1-(4'-t.-butylphenoxy)-propanol-(2).7. A method for treating hyperlipemia which comprises administering to asubject in need of such treatment, a therapeutically effective dose of acompound according to claim 1.